TRAF3IP2-IL-17 Axis Strengthens the Gingival Defense against Pathogens.

Recent genome-wide association studies have suggested novel risk loci associated with periodontitis, which is initiated by dysbiosis in subgingival plaque and leads to destruction of teeth-supporting structures. One such genetic locus was the tumor necrosis factor receptor-associated factor 3 interacting protein 2 (), a gene encoding the gate-keeping interleukin (IL)-17 receptor adaptor. In this study, we first determined that carriers of the lead exonic variant rs13190932 within the locus combined with a high plaque microbial burden was associated with more severe periodontitis than noncarriers. We then demonstrated that TRAF3IP2 is essential in the IL-17-mediated CCL2 and IL-8 chemokine production in primary gingival epithelial cells. Further analysis suggested that rs13190932 may serve a surrogate variant for a genuine loss-of-function variant rs33980500 within the same gene. null mice () were more susceptible than wild-type (WT) mice to the -induced periodontal alveolar bone loss. Such bone loss was associated with a delayed clearance and an attenuated neutrophil recruitment in the gingiva of mice. Transcriptomic data showed decreased expression of antimicrobial genes, including , , and , in the mouse gingiva in comparison to WT mice prior to or upon oral challenge. Further 16S ribosomal RNA sequencing analysis identified a distinct microbial community in the mouse oral plaque, which was featured by a reduced microbial diversity and an overabundance of genus bacteria. More was observed in the mouse gingiva than WT control animals in a ligature-promoted invasion model. In agreement, neutrophil depletion resulted in more local gingival tissue invasion by . Thus, we identified a homeostatic IL-17-TRAF3IP2-neutrophil axis underpinning host defense against a keystone periodontal pathogen.